Stereoselective recognition of the enantiomers of phenglutarimide and of six related compounds by four muscarinic receptor subtypes

Abstract

1 We have compared the binding properties of the enantiomers of phenglutarimide (1) and of six related compounds to M, receptors in NB-OK-1 cells, M2 receptors in rat heart, M3 receptors in rat pancreas and the M4 receptors of rat striatum, with their functional (antimuscarinic) properties in rabbit vas deferens (MI/M4-like), guinea-pig atria (M2) and guinea-pig ileum (M3) receptors. The binding properties of the enantiomers of three of the compounds were also measured on cloned human ml-m4 receptors expressed by CHO cells, using [3H] 3 The pA2 values at the inhibitory heteroreceptors in the rabbit vas deferens, and at the guinea-pig atria and ileum for the seven more potent enantiomers were compatible with the previous classification of these receptors as MI/M4-like, M2 and M3, respectively. 4 Replacement of the phenyl by a thienyl ring or of the diethylamino by a piperidino group in the phenglutarimide molecule did not affect markedly the potencies of the high affinity enantiomer. In contrast, replacement of the phenyl by a cyclohexyl ring decreased 20 fold the active enantiomers potency. Methylation of the piperidine-2,6-dione nitrogen also reduced markedly the eutomers' affinities, more on the M, than on the other subtypes. 5 The selectivity profiles (recognition of four receptor subtypes) of six of the seven less active enantiomers were different from the corresponding more active enantiomers selectivity profiles, suggesting that the preparations used in this study were pure. However, we cannot not exclude the hypothesis that the batch of (S)-thienglutarimide used in this study was contaminated by less than 0.02% of the eutomer. 6 In contrast with the eutomer binding site, replacement of the phenyl ring by a thienyl or cyclohexyl ring did not affect binding of the low affinity enantiomers to the muscarinic receptor or the [3H]-NMSreceptor complex. The replacement of the diethylamino group by a piperidine ring, and N-methylation of the piperidine-2,6 dione moiety increased slightly these enantiomers' potencies. 7 The muscarinic receptors were extremely stereoselective, and had up to 20 000 fold lower affinity for the less active enantiomers. However, the stereochemical requirements of the muscarinic receptor subtypes were different for the enantiomers of compounds 1-7, being most stringent at M, receptors. 8 The weaker enantiomers behaved as competitive antagonists in pharmacological studies, at least in the concentration-range investigated.

3-(1H-indol-3-yl)-2-[3-(4-nitrophenyl)ureido]propanamide enantiomers with human formyl-peptide receptor agonist activity: Molecular modeling of chiral recognition by FPR2

“…Recently it was postulated that FPRs expressed in the vomeronasal organs of mammals have an olfactory function associated with the identification of pathogenic states [35], and Bufe et al [36] found that these receptors exhibited stereo-selective preference for peptides containing D-amino acids. Although numerous GPCR have been characterized as enantioselective receptors [18;19;37], including odorant receptors [38], only one example of enantioselective recognition of non-peptide ligands by FPRs has been observed previously [9]. The growing evidence implicating anti-inflammatory and tissue-protective effects of FPR agonists [16;17] and the recent development of novel chiral ligands as potential therapeutics and agonists of various GPCR [18;19;39] prompted us to search for novel non-peptide small-molecule enantiomeric FPR agonists [12;15].…”

Analysis of the muscarinic receptor subtype mediating inhibition of the neurogenic contractions in rabbit isolated vas deferens by a series of polymethylene tetra‐amines

“…The rabbit vas deferens has been one of the most used preparation for the putative muscarinic M 1 receptor ( Eltze, 1988 ; Eltze & Figala, 1988 ). However, emerging evidence indicates that the prejunctional rabbit vas deferens muscarinic receptors mediating inhibition of the neurogenic contractions may not belong to the M 1 subtype ( Caulfield & Brown, 1991 ; Caulfield, 1993 ; Sagrada et al ., 1994 ; Waelbroeck et al ., 1996 ). A possible explanation for the confusion arising in receptor classification may be that putative muscarinic M 1 receptors have long been identified as the sites which bind pirenzepine with high affinity ( Hammer et al ., 1980 ).…”

Receptor binding studies of soft anticholinergic agents

“…Cloned receptors have been used to determine the potency of novel compounds and to determine the subtype selectivity of antimuscarinic agents (30)(31)(32). Currently, several muscarinic receptor subtype-selective agents are in advanced clinical trials (33,34).…”